Lecture 20: Challenges in antimicrobial development

Question 1

What role do antibiotics have in enabling medical advances?

Answer 1

• Organ transplants- patients are more susceptible to infections.
• Surgery: patients are at risk for surgical site infections, antibiotics are needed to prevent infections.
• Dialysis for advanced kidney disease: patients are at a higher risk of infection.
• Cancer care: patients recieving chemotherapy are at a higher risk for developing an infection during treatment.

Question 2

What are the main reasons/causes for antimicrobial resistance?

Answer 2

1. Overuse in humans favours resistance selection.
2. Poor agricultural practices selct for resistances.
   - Used as growth promoters and as a replacement for proper hygiene (Cheaper to use antibiotics).

Question 3

What are the major factors affecting antimicrobial development?

Answer 3

1. Scientific difficulty: mode of action, activity spectrum, oral requirement.
2. Economic return on reasearch and development investment (currently negative): antibiotics are reserved for last resort, patent life, approved indications, pricing

Question 4

1. What are the main steps invloved in drug discovery and development?
2. What is the chance of success of a drug being approved?

Answer 4

Drug discovery involves:

-Target identification and validation, hit identification, lead generation and optimizatoin and finally identification of a candidate for further development.

Drug development involves:

• Optimization of chemical synthesis and its formulation, toxocological studies in animals, clinical trials and eventually regulatory approval.

Chance of success is very low, and the cost accumulates .

Question 5

1. What are phase III studies and what is its purpose?

Answer 5

• Phase III studies of a clinical trial are randomized controlled studies on a large number of candidates who have the condition that the drug is meant to treat (300-3000).
• The main purpose of phase III trials is to evaluate how the new medication works in comparison to the existing medications for the same condition.

Question 6

1. Why is it diffcult to conduct phase III studies on antimicrobials that may target resistant organisms?
2. What trials are usually done instead?
3. How do we get evidence for anti-MDR activity?

Answer 6

• It is difficult and expensive to enrol thousands of patients that are needed for statistical significane because the target organism is still rare.
• The target organism are resistant pathogens.
• Non-inferiority studies are done against the most widespread pathogens at the time of the trial,not MDR or XDR (resistant strains).
• Evidence for anti-MDR activity is obtained from small salvage studies and in vitro and animal studies.
• Salvage studies are carried out on patients that have not responded to any other treatments.

Question 7

What are non-inferiority (NI) trials and when are they used?

What is the null hypothesis in NI trials?

Answer 7

• NI trials- a study that tests whether a new treatment is not worse/provides atleast the same benefit (non-inferior) than an active treatment it is being compared to.
• The null hypothesis is that the new treatment’s efficacy is worse than that of the best available treatment (BAT), on an agreed clinical end-point, by a specified margin at a given level of significance.
• Rejection of null hypothesis leads to claims of non-inferiority.

Question 8

What is the non-inferiority margin?

Answer 8

• NI margin- the difference in efficacy between the test drug and best available treatment (BAT).
• Margin is based on past variability responses to BAT when compared to placebo
• New treatment must have advantages over BAT to be approved.
• If NI margin = 0, no difference in efficay between treatments.

Question 9

What are superiority trials?

Why are non-inferiority trials used more than superiority trials?

Answer 9

• The use if superiority trials imply that the new compound/treatment is obviously better than the current treatment.
• In drug resistance, the only way to prove this is when most patients have the drug resistant infection and do not respond to/fail current treatment.
• To fail treatment in this case means death and it would be unethical to wait till patients are dying because the current treatment doesn’twork, so we have to develop treatments that are equally effective against infections we have today as most infections are not yet drug resistant.

Question 10

Are all approved drugs available on the market?

Answer 10

• No, a drug may be approved but not marketed.
• Generally a new treatment will not be used until the best available treatment fails in more than 10% of patients.

Question 11

1. What is the major institution involved in current antimicrobial research and development (R&D)?
2. Why does antimirobial R&D lead to economic failure?

Answer 11

• Small and medium-sized enterprises.
• Revenue of latest marketed antimicrobials<<<< than R&D and post-launch costs.
• On average, around 7 years before an antibiotic pays for the annual costs of keeping it on the market.

Question 12

What is meant by the “upside-down” economic model for antimicrobials?

Answer 12

• Novel antimicrobials are reserved until older ones stop functioning.
• Currently no economic viable path to develop new antimicrobials.

Question 13

What are some potential solutions for reinvigorating the antibiotic pipeline?

Answer 13

• Public-private partnerships.
• Support and pay R&D costs in novel antimicrobials.
• Reward market entry by a company.
• Purchase an agreed number of doses in advance.
• Purchase a license to use when needed.
• Value of novel agent to be calculated by public health authorities.